Systematic review brings awareness to treat-and-extend for AMD

By Michelle Dalton, ELS

A well-known dilemma surrounding age-related macular degeneration (AMD) is that there lacks a universally accepted treatment regimen with the anti-vascular endothelial growth factor (anti-VEGF) injections.

The balance between optimal visual outcomes and treatment burden (including cost) has led some retina specialists to embrace the treat-and-extend regimen in lieu of monthly treatments. One of the more comprehensive overviews on AMD published in the last year¹ reviewed evidence from both clinical trials and “real-world data” to determine how effective this particular treatment regimen is.

According to the authors, the PIER and EXCITE trials failed to achieve equal vision outcomes when anti-VEGF drugs were dosed quarterly compared to monthly dosing. SUSTAIN study was only successful with pro re nata [i.e., "as needed"] (PRN) dosing. Moving forward, a meta-analysis on CATT, HARBOR, and IVAN trials found patients on a PRN treatment had slightly significantly worse best corrected visual acuity (BCVA) and an increased risk of adverse events.

There have been prospective studies and clinical trials as well, the authors noted. For instance, Toalster et al. conducted a 12-month, open-label, nonrandomized, multicenter prospective trial using ranibizumab (Lucentis, Genentech) to access a treat-and-extend regimen using the same entry exclusion criteria as in the PrONTO trial.

Bottom line? A 9.3-letter improvement at 12 months with an average of 8 injections.

Similar results

Findings of Abedi et al. were similar using a treat-and-extend regimen with ranibizumab or bevacizumab (Avastin, Genentech). At 24 months, 95% of subjects lost fewer than 15 letters and almost 30% gained 15 letters, all with an average 9.6 and 5.7 injections in year 1 and year 2.

The LUCAS study used a treat-and-extend regiment to compare ranibizumab to bevacizumab. At 1 year, outcomes were equivalent between the 2 arms, but those in the bevacizumab arm tended to require injections every 4 weeks compared to those in the ranibizumab arm that only needed injections every 12 weeks.

The TREX-AMD prospective study on ranibizumab evaluated the treat-and-extend regimen after the 3-monthly, dose-loading treatments and found 15% and 25% of subjects gained 15 letters or more in the monthly and treat-and-extend regimens, respectively. At 24 months, outcomes were similar, prompting the authors to note “interval duration may be related to the wide range of individual VEGF suppression times and subsequently to an individual’s maximum tolerated dosing interval.”¹

ATLAS study evaluated treat-and-extend in a cohort treated with aflibercept (Eylea, Regeneron Pharmaceuticals), and found an average 11-letter gain after 2 years with a mean 5.9 injections.

‘General agreement’ found

Outside the United States, an Australian study (Essex et al.) found “general agreement” that monthly injections until lesions are no longer active is warranted, with an acknowledgement that further management was subject to a variety of subtle variations in clinicians’ approach to the disease.

Real-world data from an anonymized Fight Retinal Blindness registry found an average 7.5 injections in year 1 and 5.5 injections in year 2 (of interest, while all three anti-VEGF drugs were evaluated, only aflibercept was not used as monotherapy). However, 10% of patients had a 15-letter loss by month 24.

Mrejen et al. retrospectively evaluated patients who were on a treat-and-extend regimen for 72 months. Retention rates continually declined from 100% at year 1 to only 13% at 6 years. At 5 years, there was a decline in mean acuity that almost approached baseline levels.

Rayess et al. followed patients on a treat-and-extend regimen of either bevacizumab or ranibizumab for 3 years. At year 1, 95% of patients lost fewer than 3 lines of BCVA; by year 3, that had declined to 92%. However, at years 1 and 3, 36% of subjects had gained 3 lines of BCVA.

Throughout the study, just over 50% of the subjects had persistent choroidal neovascularization activity (based on optical coherence tomography [OCT]). Overall mean injections for years 1, 2, and 3 were 7.6, 5.7, and 5.8 respectively.

The authors of the meta-analysis noted that while the Rayess et al. paper showed a “significant gain in visual acuity” could be achieved with fewer visits, a disconcerting weakness of the study was the large number of patients who were either lost to follow-up or who exited the study after the first year.

Variability in regimens

A U.K. study evaluated electronic case review of consecutive treatment-naïve patients with AMD who were treated with aflibercept over a 2-year period. This “first real-world study to evaluate long-term visual acuity- and OCT-based retinal morphology outcomes”¹ found an expected variability in treatment regimens, but only 10% lost 15 letters by the end of the follow-up period and 22% had gained 15 letters or more with a mean of 13.5 injections over the 2-year period.

Barthelmes et al. reported the 24-month outcomes in patients receiving aflibercept as the only anti-VEGF treatment (Of the initial 212 treatment-naïve patients, 16 switched to ranibizumab during the study time frame and were excluded from analysis). A mean of 7.8 injections were received in the first year, dropping to 5.7 in the second; 98% of patients with a baseline of 70 letters maintained this acuity at study completion. Only 7% of patients lost 15 letters.

The meta-analysis authors noted that patients who switched treatments had higher baseline visual acuity and a higher proportion with good vision.

Several smaller-scale, real-world studies also have been published, but most of those are without a control arm (i.e., no head-to-head comparison), and follow-up is relatively short.¹

Gemenetzi and Patel¹ note that beyond the dose-loading phase, there is no standard regimen for dosing with an anti-VEGF. However, the treat-and-extend regimen studies “are encouraging, as it seems that the number of injections and visits can be reduced without negatively affecting visual function.”

What future studies may delineate is the appropriate time to shorten or lengthen intervals in the treat-and-extend regimen, with most studies discussed relying upon the accumulation of new fluid or persistent fluid on OCT imaging.

Reference:

1. Gemenetzi M, Patel PJ. A systematic review of the treat and extend treatment regimen with anti-VEGF agents for neovascular age-related macular degeneration. Ophthalmol Ther. 2017;6:79-82.